Ring-fluorinated imidazoles show widespread and significant activity as enzyme substrates. 2-Fluorohistidine, but not the 4-fluoro isomer, is rapidly incorporated into newly synthesized animal or bacterial protein, in place of histidine. The resulting enzymes may be structurally intact, but some cannot function catalytically because the pK of the imidazole ring has been greatly depressed. 2-fluorohistidine also serves to produce leucopenia, temporary regression of the mouse spleen, thymus, lymph nodes, and hypocellularity of the bone marrow. In mice infected with leukemia virus P-388, this analog prevents the normally massive increase in leukocyte levels and increases survival time up to 50%. Ultimate death may be due to causes other than leukemia. This anti-leukemic action may be unrelated to production of false protein, and may result from a block in the utilization of histidine as a one-carbon donor in purine biosynthesis. The block would result from the powerful inhibition of urocanase by 2-fluorourocanic acid, a metabolite of 2-fluorohistidine.